Preterm birth remains a major cause of neurodevelopmental disability. Significant cognitive handicaps are reported in over one third, and at age 8 years, more than 50% require special assistance in the classroom, 20% are in special education, and 15% have repeated at least one grade in school. During the past 7 years we have developed and characterized the clinically-relevant neonatal rodent model of chronic sublethal hypoxic injury to developing brain. Similar to findings in preterm infants, this model is characterized by both neuropathologic changes and alterations in behavior in exposed pups. We hypothesize that the chronic sublethal hypoxia that accompanies preterm birth results in dysnchrony of maturation of the preterm brain. This dysynchrony is characterized by the inappropriate phasing of both early and late developmental programs and results in long-term changes in corticogenesis in the developing brain. These long-term changes are due to altered programs of both cell maturation and cell replacement and repair. The Iongterm goal of this program is to improve the lives of very low birth weight preterm infants. Our application is composed of 4 projects and 1 core. The aim of Project 1 is to characterize the expression of neurotrophic, neurotransmitter and vascular receptors on neurons and endothelia in the developing brain to characterize the signaling interactions between them. Project 2 will examine the generation and death of newly-generated cells in the developing brain exposed to our injury designed to mimic preterm birth. The aim of Project 3 is to define the extent to which the loss of oligodendrocyte Nogo/myelin-associated glycoprotein control of axon outgrowth contributes to the deficits found in the neonatal rodent model of chronic sublethal hypoxia. Project 4 will examine the molecular mechanisms by which hypoxia results in the dysregulation of cytoskeletal pathways in the developing brain. If the central hypothesis of our program is verified, then novel therapeutic approaches for the reduction of neurodevelopmental deficits in preterm infants may result.